Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E Muhammad Ali Blvd, Louisville, KY, 40202, USA.
Department of Ophthalmology, Second Xiangya Hospital of Central South University, Changsha, China.
Stem Cell Res Ther. 2020 Mar 31;11(1):142. doi: 10.1186/s13287-020-01651-5.
Retinal degeneration is a leading cause of blindness in the world; its etiology is complex and involves genetic defects and stress-associated aging. In addition to gene therapies for known genetically defective retinal degeneration, cellular therapies have been widely explored for restoring vision in both preclinical animal models and clinical trials. Stem cells of distinct tissue sources and their derived lineages have been tested for treating retinal degeneration; most of them were reported to be effective to some extent in restoring/improving deteriorated vision. Whether this visual improvement is due to a functional integration of grafted cells to substitute for lost retinal neurons in recipients or due to their neuroprotective and neurotrophic effects to retain recipient functional neurons, or both, is still under debate.
We compared the results of subretinal transplantation of various somatic cell types, such as stem cells and differentiated cells, into Rho mice, a retinal degeneration model for human retinitis pigmentosa (RP) by evaluating their optokinetic response (OKR) and retinal histology. We identified some paracrine factors in the media that cultured cells secreted by western blotting (WB) and functionally evaluated the vascular endothelial growth factor Vegfa for its potential neurotrophic and neuroprotective effects on the neuroretina of model animals by intravitreal injection of VEGF antibody.
We found that live cells, regardless of whether they were stem cells or differentiated cell types, had a positive effect on improving degenerating retinas after subretinal transplantation; the efficacy depended on their survival duration in the host tissue. A few paracrine factors were identified in cell culture media; Vegfa was the most relevant neurotrophic and neuroprotective factor identified by our experiments to extend neuron survival duration in vivo.
Cellular therapy-produced benefits for remediating retinal degeneration are mostly, if not completely, due to a paracrine effect of implanted cells on the remaining host retinal neurons.
视网膜变性是世界范围内导致失明的主要原因；其病因复杂，涉及遗传缺陷和与应激相关的衰老。除了针对已知遗传性视网膜变性的基因治疗外，细胞疗法已广泛用于临床前动物模型和临床试验中恢复视力。不同组织来源的干细胞及其衍生谱系已被用于治疗视网膜变性；大多数研究报告在一定程度上有效，可恢复/改善视力下降。这种视觉改善是由于移植细胞的功能整合替代接受者中丧失的视网膜神经元，还是由于其神经营养和神经营养作用保留接受者的功能性神经元，或者两者兼而有之，仍存在争议。
我们通过评估 Rho 小鼠的视动反应（OKR）和视网膜组织学，比较了各种体细胞类型（如干细胞和分化细胞）经视网膜下移植到 Rho 小鼠（一种人类色素性视网膜炎（RP）的视网膜变性模型）后的结果。我们通过蛋白质印迹（WB）鉴定了培养细胞分泌的一些旁分泌因子，并通过玻璃体内注射 VEGF 抗体，对血管内皮生长因子 Vegfa 对模型动物神经视网膜的潜在神经营养和神保护作用进行了功能评估。
我们发现，无论活细胞是干细胞还是分化细胞类型，经视网膜下移植后对变性视网膜都有积极的改善作用；疗效取决于其在宿主组织中的存活时间。我们在细胞培养物中鉴定出一些旁分泌因子；Vegfa 是我们的实验鉴定出的最相关的神经营养和神保护因子，可延长体内神经元的存活时间。
细胞疗法对治疗视网膜变性的有益作用主要（如果不是完全的话）是由于植入细胞对剩余宿主视网膜神经元的旁分泌作用。
